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Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor.
No full textThe discovery of DFV890 ((R)-1), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The (R)-enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R)-1), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R)-1) was also effective in an air pouch model of gout
The solute carrier superfamily interactome
No full textSolute carrier (SLC) transporters form a protein superfamily that enables transmembrane transport of a wide range of substrates, including nutrients, vitamins, ions and drugs. There are about 450 different SLCs, residing in cellular and a variety of subcellular membranes, and playing a vital role in cellular homeostasis and metabolic regulation. Loss-of-function of an unusually high proportion of SLC transporters is genetically associated with a plethora of human diseases, making them a rapidly emerging but challenging drug target class. Knowledge of the protein environment of transporters may elucidate the molecular basis for their functional integration with metabolic and cellular pathways and help conceive pharmacological interventions based on modulating proteostatic regulations, including functional restauration. We aimed at obtaining a global survey of the SLC protein interaction landscape by using a robust standardized one-step AP-MS protocol. We mapped the protein-protein interactions of 396 SLCs, covering thousands of novel relationships, to be assessed individually in the future using transporter-specific assays. Network and clustering analysis allowed to identify proteins likely to affect the proteostatic regulation of transporters. We employed a streamlined functional assessment process based on RNA interference (RNAi)-genetic perturbation of cells and measurement of protein stability and localization, including some transports assays, to positively validate the functional role of over 50 new interactions. As an example, we detail the role of a SLC16A6 phospho-degron in recruitment of an SKP1-CUL1-F-box protein E3 ligase, and the contributions of PDZ-domain proteins LIN7C and MPP1 to the subcellular localization of SLC43A2. Overall, our work provides insights into the complex molecular network of membrane transporters while offering the largest experimental mass spectrometry-derived membrane proteins data set to date as a resource for the scientific community
Development of a Physiologically Based Biopharmaceutics Model (PBBM) Report Template: Considerations for Improved Quality in View of Regulatory Submissions
No full textPharmaceutical innovators and generic companies use Physiologically Based Biopharmaceutics Models (PBBMs) to guide drug product development and potentially waive clinical pharmacokinetic studies for both pre- and post-approval changes. This modelling approach can assist with biopharmaceutics risk assessment and the establishment of patient centric, clinically relevant drug product specifications. However, the variability of possible model strategies and the existence of gaps in scientific knowledge associated with the lack of standardized regulatory expectations for model parameterization, data requirements for model development, and criteria for fit-for-purpose model validation leads to varied acceptance rates and frequent requests for additional information and deficiencies in PBBM submissions across regulatory agencies. During the 2023 M-CERSI PBBM Best Practices for Drug Product Quality: Regulatory and Industry Perspectives workshop, it was identified that a PBBM report template summarizing model considerations and proposing a structure for presenting question(s) of interest, model context, input data, modeling plan and validation, would be beneficial for both industry and regulatory agencies. The present work is not a regulatory guideline but rather a summary of current best practices and considerations for PBBM submissions. The associated template can be downloaded directly from the supplementary information containing help text to guide preparing PBBM reports. The current manuscript discusses the critical elements of the PBBM report template which were identified during the industry-regulators scientific collaboration and interactions
Translation of Nickel-Catalyzed C(sp2)-C(sp3) Cross-Electrophile Coupling to Non-Amide Solvents
No full texthe cross-electrophile coupling of organobromides iswidely utilized in organic synthesis but generally requires undesirableamide solvents (e.g., DMF, DMA, and NMP). We report that thecombination of a strongly donating, bidentate nitrogen ligand, LiI, and4-picoline enables coupling in a variety of alcohol, ester, and etherealsolvents at up to 50 g scale. An improved synthesis of the optimalligand, 4,4′-bis(dimethylamino)-2,2′-bipyridine, is also reported on thebasis of the reductive homocoupling of 4-dimethylamino-2-chloropyridin
Futility Analyses for the MCP-Mod Methodology Based on Longitudinal Models.
No full textThis article discusses futility analyses for the MCP-Mod methodology. Formulas are derived for calculating predictive and conditional power for MCP-Mod, which also cover the case when longitudinal models are used allowing to utilize incomplete data from patients at interim. A simulation study is conducted to evaluate the repeated sampling properties of the proposed decision rules and to assess the benefit of using a longitudinal versus a completer only model for decision making at interim. The results suggest that the proposed methods perform adequately and a longitudinal analysis outperforms a completer only analysis, particularly when the recruitment speed is higher and the correlation over time is larger. The proposed methodology is illustrated using real data from a dose-finding study for severe uncontrolled asthma
Randomization-Based Inference for MCP-Mod.
No full textDose selection is critical in pharmaceutical drug development, as it directly impacts therapeutic efficacy and patient's safety of a drug. The Generalized Multiple Comparison Procedures and Modeling approach is commonly used in Phase II trials for testing and estimation of dose-response relationships. However, its effectiveness in small sample sizes, particularly with binary endpoints, is hindered by issues like complete separation in logistic regression, leading to non existence of estimates. Motivated by an actual clinical trial using the MCP-Mod approach, this paper introduces penalized maximum likelihood estimation (MLE) and randomization-based inference techniques to address these challenges. Randomization-based inference allows for exact finite sample inference, while population-based inference for MCP-Mod typically relies on asymptotic approximations. Simulation studies demonstrate that randomization-based tests can enhance statistical power in small to medium-sized samples while maintaining control over type-I error rates, even in the presence of time trends. Our results show that residual-based randomization tests using penalized MLEs not only improve computational efficiency but also outperform standard randomization-based methods, making them an adequate choice for dose-finding analyses within the MCP-Mod framework. Additionally, we apply these methods to pharmacometric settings, demonstrating their effectiveness in such scenarios. The results in this paper underscore the potential of randomization-based inference for the analysis of dose-finding trials, particularly in small sample contexts
A Phase 2 (2a) randomized trial of iscalimab in adolescents and young adults with new onset type 1 diabetes.
No full textPurpose:
Iscalimab is a fully human, monoclonal anti-CD40 antibody that blocks CD154-induced CD40 signaling.
Method:
In a Phase 2 (2a) study, new-onset stage 3 type 1 diabetes mellitus (T1DM) participants were randomized 2:1 to iscalimab or placebo administered as a single intravenous dose followed by weekly subcutaneous injections for 1 year to evaluate safety and effects on β cell function.
Results:
At 14 centers in 6 countries, 44 participants (29 M/15 F, mean age 16 years [range 12–21 years]) were randomized; 39 completed the study (26 active:13 placebo). Treatment was discontinued prematurely in seven, two of these due to a temporary trial halt during the COVID-19 pandemic. No difference in C-peptide area under the curve (C-peptide(AUC)) during a mixed meal tolerance test was observed after 52 weeks (ratio active:placebo 1.173 [80% confidence interval (CI) 0.94, 1.47], P(one-sided) = 0.18). The yearly rate of change of normalized stimulated C-peptide(AUC) suggests a slower decline of β cell function: iscalimab −0.14 (80% CI −0.23, −0.05) versus placebo −0.33 (−0.42, −0.23) nmol/L per year (P(one-sided) = 0.04). The estimated geometric mean ratio to baseline of hemoglobin A1c at week 52 was lower with iscalimab than placebo (0.95 [80% CI 0.92–0.99] versus 1.05 [80% CI 1.00–1.11], respectively). Leukocytes, neutrophils, and monocytes were lower, whereas T and B lymphocytes were higher in iscalimab-treated participants compared with placebo. Iscalimab was generally safe and well tolerated. Five serious adverse events (AEs) occurred under iscalimab (urinary tract infection, diabetic metabolic decompensation, traumatic fracture, hypoglycemia, and large intestine infection [3.4% each]) and one under placebo (mastoiditis [6.7%]). The most common AEs were hypoglycemia, nasopharyngitis, injection site reaction, COVID-19, and neutropenia. The majority of AEs were mild-to-moderate in intensity and resolved.
Conclusion:
Iscalimab has an acceptable safety and tolerability profile. The sample size limits interpretation of efficacy results. CD40:CD154 inhibition warrants further investigation in T1DM.
Trial registration: ClinicalTrials.gov Identifier: NCT04129528
Funding: Novarti
Case History: Discovery and Development of the PI3Kδ-Selective Inhibitor Joenja® (Leniolisib, CDZ173) as a Targeted Therapy for Patients with Activated PI3Kδ Syndrome (APDS)
No full textno abstrac
Induced pluripotent stem cell-derived human macrophages as an infection model for Trypanosoma cruzi.
No full textChagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people globally. Unfortunately, the available treatment options, especially for the chronic stage of the disease, are suboptimal. Given the chronic nature of the disease and the elusive nature of the parasite, there is a high need for new and safer drugs that deliver sterile cure. Posaconazole was a promising lead in the drug discovery pipeline but ultimately failed in clinical trials due to patient relapses. This failure illustrates the need for a drug screening assay that can predict sterile cure by assessing recrudescence after treatment. Here, we used human induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) as host cells for T. cruzi. The iMACs were highly susceptible to infection by the parasites. By combining red fluorescent protein (RFP)-expressing iMACs with mNeonGreen-expressing T. cruzi, we were able to monitor the dynamics of the infection through live cell imaging. The activity of the compounds benznidazole and posaconazole was consistent with the results of an established infection system using mouse primary macrophages. The post-mitotic nature of iMACs makes them suitable host cells for long-term assays needed to assess recrudescence of parasites. Moreover, their human origin, stable genetic background, and capacity for genetic modification make the iMACs excellent host cells for studying host-pathogen interaction
Master thesis proposal: Advancing non-invasive methods for evaluating therapeutic oligonucleotide efficacy in preclinical and clinical samples
No full textNovartis offers a project for a master’s student of the University of Basel interested in molecular biology and translational medicine focusing on novel therapeutic modalities.
Oligonucleotide therapeutics have emerged as precision medicines for previously untreatable diseases, by reducing gene expression through targeted mRNA cleavage. During drug development, defining the quantitative relationship between the dose and the extent of mRNA knockdown is pivotal to define a therapeutic window. Because oligonucleotide therapeutics act inside cells within specific organs, pharmacodynamic assessments often require tissue biopsies. Non-invasive approaches can reduce animal use and patient burden.
All cells release various types of extracellular vesicles (EVs) - including exosomes that carry nucleic acids, proteins, metabolites, and lipids reflecting the physiological state of their cells of origin. This enables liquid biopsy approaches that provide molecular information from tissues in a minimally invasive way.
This master’s thesis builds on proof-of-concept data validating the feasibility of approach and offers hands-on experience in advanced bioanalytics within the state-of-the-art laboratories of Pharmacokinetics Sciences. If you are interested in exosome isolation, multiplex digital PCR, transcriptome profiling, and ligand binding assays, and in enhancing your skills in experimental design, data analysis, and scientific communication, please contact us